Hematopoietic stem cell transplantation has been used for the treatment of many different malignant and nonmalignant diseases. More than 20,000 transplants have been carried out as of 1994, and the number is steadily increasing. The immune system of transplant recipients must be regenerated from the transplant inoculum, and it is not surprising that many transplant recipients are deficient in generating specific antibody responses to exogenous stimuli. This B cell immunodeficiency in these patients is associated with clinically significant infections, although the underlying mechanism remains unknown. The experiments outlined in this proposal will test the hypothesis that the B cell deficits involve a reduced capacity either of peripheral B cells to differentiate into memory cells, or of secondary lymphoid organs to support the differentiation of B cells into memory cells. The first aim will assess the recovery of a phenotypically identifiable memory B cell compartment following transplant. The results will be subject to multivariate analysis in order to define transplant variables that influence recovery of the memory B cell compartment. The second aim will assess immunoglobulin diversification in vivo, as measured by somatic mutation of rearranged variable region genes. The third aim will measure the in vitro accumulation of somatic mutation to test directly the hypotheses that B cells from some transplant recipients exhibit a defective capacity to acquire somatic mutations, or that T cells from some transplant recipients exhibit a defective capacity to induce somatic mutation in B cells. These studies are likely to provide insight into mechanisms that regulate peripheral B cell differentiation, and may lead to strategies for improving recovery of humoral immunity after hematopoietic stem cell transplantation.